Leukemia, Juvenile MyelomonocyticPhase 1/2NCT05849662
A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia
A Phase 1/2 study testing Trametinib, Azacitidine and Fludarabine in people with Leukemia, Juvenile Myelomonocytic and JMML, run by Therapeutic Advances in Childhood Leukemia Consortium at 21 sites in United States.
Trial summary
This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. Read more about this study
- Who is it for?
- Ages 1 month to 21 years
- Conditions the study is for
- Leukemia, Juvenile Myelomonocytic, JMML, JCML
- What is being tested?
- Trametinib, Azacitidine and Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 58 participants
- Where
- 21 sitesUnited States
- Study dates
- 11 Oct 2024to Dec 2029
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Age
- Patients must be ≥ 1 month and ≤21 years of age at enrollment.
- Diagnosis • Patients must meet the 2022 International Consensus Classification criteria for JMML. The diagnosis is made based on the following criteria:.
- Clinical and hematologic features (the first 2 features are present in most cases; the last 2 are required):
- Peripheral blood monocyte count ≥ 1 × 109/L*
- Splenomegaly†
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- Blast percentage in PB and BM < 20%
- Absence of BCR::ABL1
- This monocyte threshold is not reached in approximately 7% of cases. †Splenomegaly is absent in 3% of cases at presentation.
- Genetic studies (1 finding required):
- Somatic mutation in PTPN11‡ or KRAS‡ or NRAS‡ or RRAS or RRAS2‡
- Clinical diagnosis of neurofibromatosis type 1 or germline NF1 mutation and loss of heterozygosity of NF1 or somatic biallelic loss of NF1
- Germline CBL mutation and loss of heterozygosity of CBL, or somatic mutation(s) in CBL§
- Germline mutations (indicating Noonan syndrome) need to be excluded. §Occasional cases with heterozygous splice site mutations.
- Performance Level
- Karnofsky > 50% for patients ≥ 16 years of age
- Lansky > 50% for patients < 16 years of age.
- Prior Therapy
- No prior leukemia directed therapy is permitted with the exception of:
- Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of trametinib.
- Cytoreduction with 6-mercaptopurine (6-MP) 6-MP can be initiated and continued for up to 72 hours prior to the start of trametinib.
- Intrathecal (IT) cytarabine, IT methotrexate or triple IT therapy (cytarabine, methotrexate and hydrocortisone) within 7 days of enrollment as part of a diagnostic evaluation.
- No prior hematopoietic stem cell transplant is permitted.
- Adequate Renal Function Defined as:
- Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:
- Maximum Serum Creatinine (mg/dL):
- 1 month to < 6 months old - Male: 0.4, Female 0.4
- 6 months to <1 year old - Male 0.5, Female 0.5
- 1 to < 2 years old - Male: 0.6, Female: 0.6
- 2 to < 6 years old - Male:0.8, Female: 0.8
- 6 to < 10 years old - Male: 1, Female: 1
- 10 to < 13 years old - Male: 1.2, Female: 1.2
- 13 to < 16 years old - Male: 1.5, Female: 1.4
- ≥ 16 years old - Male: 1.7, Female: 1.4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
- Adequate Liver Function Defined as:
- Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age.
- The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia and will not be evaluable for hepatotoxicity. This must be reviewed and approved by the study chair or vice chair.
- Adequate Cardiac Function Defined as:
- Ejection fraction of > or = to 50% by echocardiogram, OR
- Ejection fraction of > or = to 50% by radionuclide angiogram (MUGA).
- Reproductive Function
- Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
- Female patients with infants must agree not to breastfeed their infants while on this study.
- Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.
Who cannot join
- Patients cannot have a known allergy to any of the drugs used in the study.
- Patients cannot have a systemic fungal, bacterial, viral, or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.
- Patients cannot have a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
- Patients cannot have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
- Patients cannot have a clinical or molecular diagnosis of Noonan syndrome. Note: patients with either neurofibromatosis type 1 or Casitas B-lineage lymphoma (CBL) syndrome (also known as Noonan-like syndrome), are eligible to enroll. Patients with Down syndrome are excluded from the study.
- Patient cannot have had prior use of hematopoietic growth factors, biologics (anti-neoplastic agent), or XRT.
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- Patients cannot be taking any medications for treatment of left ventricular systolic dysfunction.
- Patients cannot have a history of or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
- Patients cannot have had prior use of any MEK inhibitor.
Trial locations and contacts
21 sites in 1 country. Contact the study team or a site near you to ask about taking part.
21 sites in 1 country
United States21 sites, 21 recruiting
- Recruiting
C.S. Mott Children's Hospital
Ann Arbor, Michigan, 48109
Jennifer Agrusa, MD
- Recruiting
Children's Hospital of Atlanta
Atlanta, Georgia, 30322
Melinda Pauly, MD
- Recruiting
Sidney Kimmel Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231
Stacy Cooper, MD
- Recruiting
Levine Children's Hospital at Carolinas
Charlotte, North Carolina, 28203
Joel Kalpan, MD
- Recruiting
Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
Jenna Rossoff, MD
- Recruiting
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Lauren Pommert, MD
- Recruiting
Children's Medical Center
Dallas, Texas, 75235
Tamra Slone, MD
- Recruiting
Children's Hospital of Colorado
Denver, Colorado, 80045
Kelly Faulk, MD
- Recruiting
Indiana University/Riley Hospital for Children
Indianapolis, Indiana, 46202
Sandeep Batra, MD
- Recruiting
Children's Mercy Hospital
Kansas City, Missouri, 64108
Keith August, MD
- Recruiting
Children's Hospital Los Angeles
Los Angeles, California, 900027
Jaime Stokke, MD
- Recruiting
St. Jude Children's Research Hospital Memphis
Memphis, Tennessee, 38105
Seth Karol, MD
- Recruiting
University of Miami
Miami, Florida, 33136
Julio Barredo, MD
- Recruiting
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Kavitha Ramaswamy, MD
- Recruiting
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Sarah Tasian, MD
- Recruiting
Phoenix Children's Hospital
Phoenix, Arizona, 85016
Dana Salzberg, MD
- Recruiting
Oregon Health & Science University
Portland, Oregon, 97239
Bill Chang, MD
- Recruiting
Primary Children's Hospital
Salt Lake City, Utah, 84113
Mallorie Heneghan, MD
- Recruiting
University of California San Francisco
San Francisco, California, 94158
Elliot Stieglitz, MD
- Recruiting
Seattle Children's Hospital
Seattle, Washington, 98105
Mignon Loh, MD
- Recruiting
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Reuven Schore, MD
About this study
Official title: Risk Stratified Treatment for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase I/II Non-randomized Study of Trametinib and Azacitidine With or Without Chemotherapy (IND #164058)
This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. High-risk JMML patients will receive trametinib, azacitidine, fludarabine, and cytarabine.
Read the detailed description
Primary Objectives:
- To determine the safety of combining trametinib with azacitidine for patients with newly diagnosed lower-risk JMML.
- To determine the safety of combining trametinib with azacitidine (Aza), fludarabine (FLA) and cytarabine for patients with newly diagnosed high-risk JMML.
Dosing:
Patients with newly diagnosed lower-risk JMML will be treated with daily azacitidine for 5 days in combination with daily trametinib for 28 days per course for up to 12 courses. Patients with newly diagnosed high-risk JMML will be treated with daily azacitidine, fludarabine, and cytarabine for 5 days in combination with daily trametinib for 28 days per course for up to 2 courses.
- Conditions
- Leukemia, Juvenile Myelomonocytic, JMML, JCML, Neurofibromatosis 1, CBL Syndrome
- Being tested
- Trametinib, Azacitidine, Fludarabine, Cytarabine
- Medical subject headings
- Leukemia, Myelomonocytic, Juvenile, Neurofibromatosis 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TrametinibDrug
Also called GSK1120212B, TMT212-NXA
PO or NG QD Days 1-28
For patients age < 6 years: 0.032 mg/kg/day at max dose = 2mg/day
For patients age ≥ 6 years: 0.025 mg/kg/day at max dose = 2 mg/day
AzacitidineDrug
Also called 5-azacytidine, Vidaza
IV over 30 minutes Days 1-5
Age < 1 year or weight <10kg:
2.5 mg/kg/day
Age ≥ 1 year and weight ≥ 10kg:
75 mg/m2/day
FludarabineDrug
Also called FLUDARA FOR INJECTION
IV over 30 minutes Days 6-10
30 mg/m2/day (1mg/kg if <12 kg)
CytarabineDrug
Also called Cytosine arabinoside, Ara-C, Cytosar
IV over 3 hours Days 6-10
2000 mg/m2/day (67mg/kg if <12 kg)
| Study group | Role | What they receive |
|---|---|---|
| Lower-risk patients | Experimental | Lower-risk patients are defined as having a mutational burden of one clonal alteration AND a low DNA methylation classification. Receives: Drug: Trametinib; Drug: Azacitidine |
| High-risk patients | Experimental | High-risk patients are defined as having as having a mutational burden of more than one clonal alteration AND/OR an intermediate or high DNA methylation classification. Receives: Drug: Trametinib; Drug: Azacitidine; Drug: Fludarabine; Drug: Cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine the safety of combining trametinib with azacitidine for patients with newly diagnosed lower-risk JMML.
The incidence of dose limiting toxicities (DLTs) after the 1st course of therapy will be measured at different dose levels.
Measured: At the end of the evaluation period of Cycle 1 (defined as 28 day cycle of therapy plus 30 days following the last dose of study therapy)
To determine the safety of combining trametinib with azacitidine (Aza), fludarabine (FLA) and cytarabine for patients with newly diagnosed high-risk JMML.
The incidence of dose limiting toxicities (DLTs) after the 1st course of therapy will be measured at different dose levels.
Measured: At the end of the evaluation period of Cycle 1 (defined as 28 day cycle of therapy plus 30 days following the last dose of study therapy)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2023
- Study start11 Oct 2024
- Primary completionDec 2028 (estimated)
- Study completionDec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Leukemia, Juvenile MyelomonocyticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Patients will be concurrently enrolled into both the lower-risk and high-risk arm starting at Dose Level 1. The rolling 6 design will be used during Phase 1 of the study to confirm the recommended Phase 2 dose, separately for the lower-risk and high-risk arm, with one possible de-escalation.
- Masking
- None (open label)
- Enrolment
- 58 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Therapeutic Advances in Childhood Leukemia Consortium
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05849662
- Sponsor's protocol ID
- T2020-004
- Status last verified
- Aug 2026
- First submitted
- 25 Apr 2023
- Last updated
- 4 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No